Challenges in the development of new antibiotics in the 21st Century

Roadblocks and Opportunities David M. Shlaes MD PhD

www.antiinfectivesconsulting.com http://antibiotics-theperfectstorm.blogspot.com/

Disclaimers
I make my living by consulting
Large PhRMA Biotech Academics

Active member of IDSA. I am NOT a statistician! Mostly working on antibiotics, occasionally antiviral drugs. A recent client list can be found on my website. The views I present today are my own.

Outline
Resistance is global.
We need a pipeline of new antibiotics active against resistant pathogens.

Companies continue to abandon the field.

FDA is releasing guidance requiring infeasible trial designs. The FDA must provide feasible guidance.
Pharmacometrics is one way forward.

The US antibiotic market share is decreasing.

It will soon make sense to ignore the US.

Novel trial designs are needed.

FDA Antibiotic Approvals 19832012

Boucher, H at Pew charitable Trust Meeting

The Perfect Storm

Antibiotic discovery is hard! The ROI is average at best. The regulatory environment (US) is hostile.

Consolidation within the pharmaceutical industry 1980-2003.

2003 Pharmaceutical Company

Aventis1 Bristol-Meyers-Squibb Glaxo Smith Kline Novartis Pfizer Wyeth2 Total
1. 2. Now Sanofi-Aventis Now Pfizer

Number of original companies since 1980

17 8 12 7 12 14 70

Large PhRMA Actively Pursuing Antibiotics R&D 2011

Astra-Zeneca GSK Sanofi-Aventis (Novartis) (Merck)

Synercid - 1999
Linezolid 1999 Daptomycin 2003 10-14 years will seem short if things dont change.

FDA vs. EU
FDA
Guidance for each indication. Establishes own breakpoints can conflict with CLSI, EUCAST. Good communication possible and encouraged. No link between regulatory process and price.
May change with Medicare

EMEA
General guidance lots of room for novel approaches. Communication encouraged but difficult formal process both sponsor and CHMP obliged by decisions.
Most sponsors use individual country agencies for communication.

Breakpoint - Individual countries decide

New process exists to allow EUCAST review of proposed breakpoints for EMEA.

Regulatory decisions linked to pricing by individual countries.

The Low Point

At the 2010 ICAAC, Mark Goldberger, former Director ODE IV at FDA, stated that our letter, Shlaes and Moellering, entitled, The FDA and the End of Antibiotics, 2002, was the low point in FDA-industry relations on antibiotics. Little did he know . . .

The Ketek Scandal

David M Shlaes, Robert C Moellering. Telithromycin and the FDA: implications for the future. Feb 2008 The Lancet Infectious Diseases, Vol. 8 No. 2 pp 83-85.

In 2006, US marketing approval for telithromycin (Ketek) for otitis, sinusitis and ABECOPD was withdrawn.
Rare but serious liver tox. They had not proven efficacy via placebo-controlled trials as is now required but was not required when S-A developed the drug.

In the wake of the Ketek scandal of 2006, congress piled-on on the FDA demanding answers as to how such a drug could have possibly been approved. The results of this unnecessary scandal have been a loss of critical FDA personnel and a subsequent lack of leadership at the FDA. consistent interference in FDAs efforts in the critical area of clinical trials for new antibiotics (GAO report) constant and unpredictable waffling by the FDA along with an antibiotic approval record that will leave our critical antibiotic pipeline in imminent danger for at least the next decade.

The Basis of Non-Inferiority

A non-inferiority trial ASSUMES that the control antibiotic (directly or indirectly) has been shown to be superior to placebo. The treatment effect = control placebo. The NI margin can never be greater than the treatment effect. To justify their NI margins, the FDA has used data from the pre-antibiotic era, or has used modern data where treatment has been inadequate, to determine a treatment effect.

Non-Inferiority Trials and Bio-Creep

Relative Efficacy in Otitis Media
100

We have always known about possible biocreep. CHMP

80

Study 2: abxA vs abxB = 8% = 8% = 8%

Study 3: abxB vs abxC

Study 1: abxA vs placebo = 20% Placebo = 60% effective

Study 4: abxC vs abxD (now equal to placebo)

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Approval based on a +/- 10% delta

John Bradley, UCSD

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FDA Discounting
To calculate the NI margin once they have defined a treatment effect the FDA then estimates the 95% confidence interval around this effect and selects the lower bound. They then apply an arbitrary discount to be sure that the NI margin does not exceed a treatment effect. (???) In this way a treatment effect of 50% always leads to an NI margin of 10%.

Tigecycline example
Indication CAP (Total Number for 2 Studies) 70% evaluability Skin (Total Number for 2 Studies) 60% evaluability IAI (Total Number for 2 Studies) 60% evaluability HAP (Total Number for 1 Study) 60% evaluability TOTAL Cure Rate 85% 90% Power 10% delta 1532 90% Power 15% delta 688

80%

2248

1000

70%

2948

1316

65%

1598 8326 80% Power 10% delta

710 3714 80% Power 15% delta 2770

TOTAL

6226

Decreasing from 90% to 80% power doubles the risk of a false negative result when the agent is actually not inferior (thanks to M. Wible)

Multiple Indications and Multiple Trials:

Implications for Program-wise Error Rate
A total of 300 evaluable patients (150 each arm) are needed to have a 90% chance to declare non-inferiority based on a 15% margin and a control cure rate of 80%. .025 .18 .58 .90

15

10

-5

10

If the approval is based on 2 independent trials, the chance of approving a drug that is truly 10% inferior than the control is < 0.18x0.18 = 0.032. If we have 3 trials, the chance is < 0.006.
Christy Chuang-Stein, Ph.D.

PhRMA why do this?

Otitis Media middle ear infection of childhood

2 very recent studies 3-5 years to complete.

DRAFT Guidance CABP 2009

Efficacy population microbiologically documented. NI margin oral drugs 10%. No prior antibiotics allowed. Assume 90% power, 85% cure, 85% clinical evaluability, 25% microbiologically documented.

CE 0.85 ME 0.25 Total of 2 trials

Total enrolled 2524 5048

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Early Endpoints required!

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CABP Guidance
Community acquired bacterial pneumonia under revision in response to an uproar from stakeholders over trial feasibility and relevance of endpoints. At a recent AIDAC meeting the FDA proposed a series of feasible designs for IV or IV-oral antibiotics. The allowance of at least limited prior antibiotic use will provide for at least some US patients to be enrolled in these trials. Oral antibiotics remain in limbo. The proposed endpoints, based on historical studies, are thought to be clinically irrelevant by many. The more relevant endpoint of cure at TOC could be justified using pharmacometrics to establish a treatment

effect and therefore a non-inferiority margin.

HABP/VABP Endpoint
The FDA has identified a body of literature that compares mortality rates after adequate vs. inadequate therapy.
Similar data for clinical outcome is not available. Therefore the endpoint is mortality at 28 d.

28 d mortality in the context of a HABP/VABP trial is a confounded variable that depends as much on comorbidities as it does on pneumonia. A more appropriate endpoint based on clinical outcomes could easily be justified using pharmacometrics why dont we take advantage of this for M1 and M2 calculations? 24

BIO 2010

Prior Antibiotic Use

Current guidance precludes use of antibiotics for months prior to HABP/VABP for enrollment in a trial. Virtually all patients in the ICU and 60-80% of patients in hospitals for any length of time receive antibiotics. Why should we try and limit our trials to outliers? We actually want to enroll patients with prior treatment into our trials to enroll patients more likely to have resistant pathogens so that we can test whether new products work as expected against such infections. Are there data that suggest that HABP/VABP patient outcomes are affected by prior antibiotic use? Data cited in the docket indicates that outcomes are affected in a negative way therefore prior use is a conservative 26 approach.

HABP/VABP is an Area of High Medical Need

Given the urgent medical need for new antibiotics to treat patients with antibioticresistant infections in this indication, why are we making it impossible to get drugs approved for Americans? Number of ongoing phase III trials for new antibiotics in HABP/VABP 0!!! But several new drugs are on the cusp of starting such trials.
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Urinary Tract Infection

The FDA just (2/23/12) released their new Draft guideance. A 10% NI margin on the microbiologically evaluable population requires a study of 23000 patients over two trials.

The proscription against all antibiotic use during the 48 hours prior to enrollment will be a significant roadblock. The guideance as it stands, is infeasible.

FDA Trial Design Agreement (SPA) Untrustworthy

After trials have been initiated or even completed based on a design agreed between the sponsor and the FDA, the FDA allows themselves the prerogative of changing their trial design requirements.
They have exercised this prerogative on several occasions. Companies have gone belly up as a result.

Going Forward
Declare an immediate moratorium on implementation of the 2009 Draft Guidance.
Go back to previous guidance while awaiting new guidance. This will eliminate the proscription against prior antibiotics as well.

Use pharmacometrics to define an M1 for HABP/VABP and derive an appropriate M2 and NI margin for clinical outcome at TOC. EMA has allowed 15-20% NI trials with a primary endpoint of clinical outcome at TOC and they are willing to discuss use of pharmacometrics.

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Indications for Anti-infectives

Total sales = $37.5B

Pharmaceutical Markets
Growing markets Stagnating (but LARGE) markets Pharmemerging
markets (China, India, Brazil, Russia, Mexico, Turkey, S. Korea) Rest of World US Europe Japan

Drivers of Lack of Growth in US

Generic Intrusion + Lack of New Products Generic Intrusion + Lack of New Products Generic Intrusion + Lack of New Products Generic Intrusion + Lack of New Products

2006 2007

2008

2009

2010

New Trial Designs

for drugs with activity against highly resistant strains Low Quantity, High Quality Mark Goldberger, FDA, 2002. Superiority
Historical controls Active controls Active plus optimized standard of care vs. SOC + placebo.

Compassionate use Conditional approval